Investigating the DNA damage response of different cell types in the normal human breast
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Rebecca Johnston
PROVIDER: E-GEOD-67595 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations in this enzyme have not been previously linked to any pathology in humans, a testament to its indispensable role in cell biology. Based on a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II, are sufficient to hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors reveal dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4. In addition to POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA and SMO, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features. Expression microarray data from 121 total samples, including 96 tumors representing the major meningioma mutation groups (NF2/chr22 loss, POLR2A, KLF4/TRAF7, PI3K mutant, Sonic Hedgehog mutant) and 25 control samples (3 dura, 13 adult meninges, and 9 embryonic meninges).
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-08-21 | E-GEOD-85135 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-11-24 | E-GEOD-56047 | biostudies-arrayexpress
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2014-05-29 | E-GEOD-58037 | biostudies-arrayexpress
Project description:Deciduous and permanent human teeth represent a model system to study ageing of mesenchymal populations. Aging is tightly connected to self-renewal and proliferation and thus, mapping potential molecular differences in these characteristics between populations constitutes an important task. Specifically designed microarray panels were used. We have detected a number of molecules that were differentially expressed in dental pulp mesenchyme from deciduous and permanent teeth extracted from young children and adults, respectively. Among the differentially regulated genes HMGA2, a stem cell-associated marker, stood out as a remarkable example with a robust expression in deciduous pulp cells. In addition to this, we discovered that several proliferation-related genes, including CDC2A and CDK4, were up-regulated in deciduous pulp cells, while matrix genes COL1A1, fibronectin and several signaling molecules, such as VEGF, FGFr-1 and IGFr-1 were up-regulated in the pulp cells from permanent teeth. Taken together, our data suggest that deciduous pulp cells are more robust in self- renewal and proliferation, whereas adult dental pulp cells are more capable of signaling and matrix synthesis. The deciduous teeth were collected from 3-12-year-old children (N=8), whereas the permanent teeth were collected from adults, 19-52 years of age (N=8). The tooth was mechanically separated into two halves to remove all soft tissue in the pulp. The pulp tissue was digested and the dissociated cells were passed through cell strainer and plated with culture medium. The cells were then passaged at 90% confluency to a 10 cm dish for expansion. RNA was extracted from passage one cells with the Qiagen RNeasy Mini Kit. Microarray analysis was performed using PIQORTM Stem Cell Microarray chip (Miltenyi Biotech), which is comprised of 942 relevant genes for stem/progenitor cells and key genes for cell differentiation, to identify gene sets that are differentially expressed between cells in the deciduous and adult teeth. A total of 1 μg RNA for each sample was used for amplification and further analysis with the PIQORTM stem cell microarray chip (Miltenyi Biotec), followed by detection with a laser scanner (Agilent Technologies). In total, 8 comparisons were performed with dataset consisting of two microarrays, each containing a total of 11 slides with signal intensities within the R/Bioconductor statistical framework. The Linear Model for Microarray Data package (Limma) was used to pre-process the raw data, perform quality controls and estimate statistical significance. Expression intensities were background-corrected using a convolution of normal and exponential distributions with an offset of 50, which were then normalized within every slide using loess normalization. We analyzed the red and green channels separately using the mixed model method and different groups were quantile-normalized separately. The correlation was computed between the two channels for the same spot. Differentially expressed genes were identified by computing the contrasts, fitting to a linear model, performing the hypothesis tests, and correcting for multiple testing by performing the false discovery rate using the Benjamini-Hochberg correction.
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Project description:The MESA Epigenomics and Transcriptomics Study has been launched to investigate potential gene expression regulatory methylation sites in humans by examining the association between CpG methylation and gene expression in purified human monocytes from a large study population (community-dwelling participants in the Multi-Ethnic Study of Atherosclerosis (MESA)). The MESA Epigenomics and Transcriptomics Study was funded by a National Heart, Lung and Blood Institute grant (R01HL101250) through the NIH Roadmap Epigenomics Program in 2009. The current study is particularly focused on the relationships between transcriptomics and methylomics with age. Data includes transcriptomic and methylomic data from CD14+ samples, collected from 1,202 individuals ranging 44 - 83 years of age (Exam 1). Peripheral monocytes were isolated from blood (Exam 5) with anti-CD14 coated magnetic beads, and the Illumina HumanHT-12 v4 Expression BeadChip and the Illumina HumanMethylation450 BeadChip were used to provide genome-wide coverage of mRNA expression and DNA methylation, respectively. This data enabled us to identify CpG loci whose degree of methylation was associated with age (age-DMR),and identify age- and expression-associated methylation sites (age-eMS), whose degree of methylation was associated with age and cis-gene expression (+/- 1Mb), after adjusting for other covariates such as race, gender, study site, and sample contaimination with B-cells, T-cells, natural killer cells, and neutrophils. To estimate residual sample contamination for monocyte data analysis, separate enrichment scores for neutrophils, B cells, T cells, and natural killer cells were calculated and provided as sample characteristics. The participant race, gender, and study site were provided as 'raceGenderSite variable' which represents a combination of those factors. A detailed description of each sample characteristics is included in the 'README.txt'.
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Project description:The MESA Epigenomics and Transcriptomics Study has been launched to investigate potential gene expression regulatory methylation sites in humans by examining the association between CpG methylation and gene expression in purified human monocytes and T cells from a large study population (community-dwelling participants in the Multi-Ethnic Study of Atherosclerosis (MESA)). The MESA Epigenomics and Transcriptomics Study was funded by a National Heart, Lung and Blood Institute grant (R01HL101250) through the NIH Roadmap Epigenomics Program in 2009. Data includes transcriptomic and methylomic data from CD4+ samples, collected from 214 individuals. Peripheral T cells were isolated from blood (Exam 5) with anti-CD4 coated magnetic beads, and the Illumina HumanHT-12 v4 Expression BeadChip and the Illumina HumanMethylation450 BeadChip were used to provide genome-wide coverage of mRNA expression and DNA methylation, respectively. This data enabled us to identifyCpG loci whose degree of methylation was associated with age (age-DMR),and identify age- and expression-associated methylation sites (age-eMS), whose degree of methylation was associated with age and cis-gene expression (+/- 1Mb), after adjusting for other covariates such as race, gender, study site, and sample contaimination with B-cells, monocytes, natural killer cells, and neutrophils. To estimate residual sample contamination for monocyte data analysis, separate enrichment scores for neutrophils, B cells, T cells, and natural killer cells were calculated and provided as sample characteristics. The participant race, gender, and study site were provided as 'raceGenderSite variable' which represents a combination of those factors. A detailed description of each sample characteristics is included in the 'README.txt'.
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